Advanced non-small cell lung cancer is incurable with a median survival of 12 mo. Incremental advances have been made over the past 20 years when the median survival was only 9 months. A major advance was the discovery of driver mutations and agents targeting these have been highly successful, however a small percentage of patients qualify. Recently it was found that immunotherapy produces clinical responses in NSCLC, and the impact appears dramatic with significant improvements of median OS, and many of the responses remaining durable. This major advance came by disrupting a single immunomodulatory pathway (PD1 checkpoint). The prospects for continuing to improve this modality are great given the fact that tumors evade immune rejection in a myriad of different ways. Here we propose for the first time to target another immune checkpoint protein that produces immunosuppression within tumors, the adenosine A2A receptor. This protein is frequently expressed on human lung cancer TILs, and the tumor microenvironment has high concentrations of its ligand, adenosine. We will utilize an adenosine A2A receptor antagonist to prevent T cell inhibition through this pathway. Single agent anti-PD1 is well tolerated and produces a RR of 15% in NSCLC, therefore we will use this as the platform onto which we will add PBF-509, an A2AR antagonist. Safety and preliminary clinical efficacy will be assessed in phase I and two arm (immunotherapy-nave, and immunotherapy resistant groups) phase Ib clinical trials.The resistance mechanisms operational in immunotherapy non-responders are currently unknown. We will perform pre- and on-treatment biopsies of the patients which will allow us to characterize the productive immune response in the clinical responders, and the nature of the resistance mechanisms in the clinical non-responders.Given the multitude of potential immunoinhibitory mechanisms co-opted by tumors, and the heterogeneity as to which of these are operational in individual patients, clinical response predictive tests are neceassary but do not currently exist for immunotherapeutics. Therefore we also propose to examine the expression of a variety of immune-related genes for preliminary performance as clinical response predictors.